Paul- Project 1 Program Director/Principal Investigator (Last, First, Middle): MacLeish, Peter R. PROJECT SUMMARY (See instructions): In today's demanding 24-hour society the prevalence of sleep disorders continues to increase; however, the development of effective treatments for those disorders has not kept pace. One of the primary reasons is that many of the genetic and molecular pathways that underlie basic sleep processes are still undefined. Forward genetics approaches have yielded novel therapeutic targets and more effective treatments for a variety of diseases; however, similar milestones in the study of sleep disorders have been elusive. It has become apparent in the last several years that the genetics of sleep are complex, involving multiple genes and gene interactions with potentially small effect sizes. Larger-scale genomic approaches are likely to provide the necessary power uncover the genes that underlie sleep processes. In this application we propose a forward genetics approach that takes advantage of natural variation occurring in inbred mice. We have characterized 53 sleep-wake phenotypes in 14 inbred mouse strains in sleep-replete and sleep-deprived conditions. We propose to expand this dataset to add a minimum of 11 additional strains to provide sufficient statistical power for quantitative trait loci (QTL) analysis and positional cloning in subsequent recombinant hybrid crosses to transition from QTL to gene. This endeavor will combine a well-established paradigm of comparative phenotyping of a genetically tractable animal model with powerful genetic mapping tools to identify novel sleep regulatory genes. Consequently, these experiments will not only identify new sleep genes, they will also help verify and clarify previously mapped genes whose roles are not yet clearly defined. Ancillary benefits of this proposal include the potential identification of practical biomarkers of sleepiness, which is often cited as one of the most pressing needs in contemporary sleep research.